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ROLE OF AUF1 PHOSPHORYLATION IN PROTEIN TURNOVER AND mRNA DEGRADATION

by
Jennifer Defren
B.S., Rutgers University - 2003




Thesis Advisor: Gary Brewer, Ph.D.
Graduate Program in Molecular Genetics,
Microbiology & Immunology

Microbiology Department Conference Room 747
RJWMS Research Tower
Piscataway

Friday, March 18, 2011
2:00 p.m.


Abstract

Many cytokines are regulated post-transcriptionally by A + U-rich elements (AREs) present in the 3 untranslated regions (UTRs) of their messenger RNAs. These labile mRNAs can be transiently stabilized by the binding of trans-acting factors to the AREs. AUF1 binds to the ARE as part of a multi-subunit complex called ASTRC (AUF1 and Signal Transduction Regulated Complex). This complex includes the proteins such as the translation initiation factor eIF4G, poly(A) binding protein (PABP), lactate dehydrogenase, and the chaperone proteins Hsc70, Hsp70, and Hsp27. Recent work shows that p38/MAPK-induced Hsp27 phosphorylation promotes AUF1 protein turnover and stabilization of ARE-containing mRNA; the mechanism is unclear. In this work, we show that the F-box protein -TrCP, the substrate recognition subunit of the SCF E3 ubiquitin ligase complex, recognizes and targets AUF1 for degradation in a proteosome-dependent manner. We also show that -TrCP-mediated turnover of AUF1 is influenced by Hsp27 phosphorylation and by phosphorylation of the p40AUF1 isoform.


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